(I) Chromosomal rearrangements are important in evolution and can lead to abnormalities in humans. Yet little is known about the molecular factors predisposing their occurrence in eukaryotes. We propose to investigate these factors at the nucleotide sequence level. A series of rearrangements resulting from unequal crossovers in the human Beta globin gene cluster will be studied. We will also examine examples of intrachromosomal gene conversions between globin genes. In each case we will determine the nucleotide sequences at the sites of the rearrangement and will look for sequences which may have initiated these apparently homologous exchanges. DNA sequences predisposing the occurrence of apparently non-homologous exchanges resulting in deletions in the Beta globin cluster will also be investigated. We hope to find out whether these exchanges are associated with breakage and reunion events at completely non-homologous sequences or at small regions of local homology, or are related to previously unsuspected factors. We will also start an investigation of the chromosomal region controlling the synthesis of the proline-rich proteins of human parotid saliva. This region appears to be an excellent new system in which to investigate chromosomal rearrangements. (II) We propose to look for a possible relationship between gene expression and gene replication in eukaryotes. Specifically, we will determine the direction in which the genes of the human Beta globin cluster are replicated in tissues which are using some of these genes and in tissues which are not. We will look for possible changes in the usage of orgins of DNA replication in relation to developmental changes in the expression of the genes. We will also attempt to identify for the first time all the origins within a specific region of the human genome.